Three-Center Nonclassical Cation in the ... - ACS Publications

Communications to the. Editor. 1867. V-T-OH. VI. As we had reasons to hope,2b reaction on the dienol. IV with 3 moles of methylene iodide and excess z...
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COMMUNICATIONS TO THE EDITOR

May 5, 1964

Q

OH

I I i

I1

V-C-OH VI1

111

I

I

+ -

V-T-OH

VI

As we had reasons to hope,2breaction on the dienol IV with 3 moles of methylene iodide and excess zinccopper couple proceeded stereospecifically to introduce two cyclopropane rings cis to each other and to the hydroxyl group.g Conversions of IV to bisadduct up to 90% were observed. The bisadduct fraction was homogeneous in V.P.C. and could be isolated by preparative v.P.c.’ Alternatively, i t can be freed from unsaturated starting material and monoadduct by extracting a pentane solution with saturated aqueous silver nitrate, after which i t crystallizes readily. After purification through the p-nitrobenzoate,6 m.p. 124.8125.4”, the tricyclo [7.1.0.05~7]decan-3-o16 V-C-OH had m.p. 57-58’, m.p. of the p-toluenesulfonate6 104-105”. The epimer of alcohol V-C-OH was obtained by chromic anhydride oxidation to the ketone6 VI, m.p. 51.552.5’, and reduction of the latter with sodium borohydride in methanol. The reduction product consisted of ‘epimeric alcohol to the extent of cu. 97%. The isolated epimer,6 V-T-OH, had m.p. 56-57’, m.p. of the p-toluenesulfonate6 70-71 O. The structure and configuration of the epimeric V-OH alcohols are clear from the spectroscopic and chemical evidence. The epimeric V-T-OH and V-C-OH display nearly identical n.m.r. spectra, with the triplet signal for the a-proton on C-3 in V-T-OH a t lower field and sharper than in V-C-OH. While the n.m.r. spectra of the alcohols suggest a cis arrangement of cyclopropane rings, there is also a compelling stereochemical argument that the cyclopropane rings cannot be trans to each other. With a trans arrangement of cyclopropane rings, only one alcohol, a dl-racemate, would be possible, instead of an epimeric pair. Oxidation of the alcohol to the ketone and subsequent reduction would simply regenerate the same alcohol. The available evidence shows that in V-C-OH the hydroxyl group is indeed cis to the cyclopropane rings, and in V-T-OH it is trans. Examination of models suggests a preferred crown-like conformation for tricycle [7.1.0.05~7]decane systems like V-C-OH and V-TOH, a substituent on C-3 being either “equatorial” or “axial.” That V-C-OH has an equatorial cis hydroxyl group and V-T-OH has an axial trans hydroxyl is clear from comparison of the n.m.r. C-3 proton signals1° for the two alcohols. the shorter V.P.C.retention time (9) For comparison, 1.4-cyclooctadiene yields a 66:34 cis-frons mixture of the parent tricyclo[7.1.0.06~7]decanes. (10) (a) R . Lemieux, et ai., J. A m . Chem. Soc., 80, 6098 (1958); (b) A. Cope. S. Moon, and C. H . Park, i b i d . , 84, 4843, 4852 (1962).

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of V-T-OH on polar columns, and the predominant formation of V-T-OH from “steric approach control” sodium borohydride reduction of ketone VI. Another route to V-T-OH is hydroboration-oxidation of the 1,3,6-~yclooctatrienebismethylene adduct VI1 with cis cyclopropane rings. This alcohol and its C-2 hydroxyl isomer arise in ca. equal proportions from this reaction.’l Acknowledgment.-We are indebted to Dr. F. Ebel of the Badische Anilin und Soda Fabrikwerke in Ludwigshafen, Germany, for generous supplies of the necessary cyclooctatetraene starting material which made this work possible. (11) J Zirner and P Bruck, unpublished work (12) U S Rubber Company Foundation Postgraduate Fellow in Physical and Engineering Science for 1961-1962

CONTRIEUTION No 1646 PHILLIPRADLICK’* OF CALIFORNIA S WINSTEIN UNIVERSITY OF CHEMISTRY DEPARTMENT Los ANGELES24, CALIFORNIA RECEIVED MARCH6, 1964

Three-Center Nonclassical Cation in the PentahomocyclopentadienylSystem’

Sir: Since the parent alcohols I-C-OH and I-T-OH in the pentahomocyclopentadienyl system are now available,* it is possible to examine the behavior of this system from the viewpoints of homoconjugation and homoaromaticity.3 , 4 This report concerns the corresponding carbonium ion intermediate in acetolysis of the toluene~ulfonate,~ I-C-OTs.

OH

OH

I-C-OH

I-T-OH

For acetolysis of I-C-OTs i t is possible to make an a priori prediction of the kind of delocalized cation to be expected. In a cyclopentadienyl species, electron delocalization must almost inevitably be over all five centers due to the rigid planar geometry, whereas the more flexible and adaptable pentahomocyclopentadienyl species present more possible patterns of electron delocalization. For the cation from I-C-OTs we should consider both three- and five-center nonclassical species such as bi~homoallyl,3~~ trishomocyclopropeny1,3~4 tetrahomopentadienyl,4 and pentahomocyclopentadieny18 types A, B, C, and D, respectively. Neglecting strain energies involved in reorganizing the carbon skeleton, the corresponding Hiickel LCAO-MO delocalization energies in units of PI, the pertinent resonance integral, are 0.824, 2.000, 1.464, and 1.236, respectively.6 (1) (a) Research sponsored by the U . S. Army Research Office (Durham). (b) Research was supported in part by a grant from the Petroleum Research Fund administered by the American Chemical Society. Grateful acknowledgment is hereby made t o the donors of this fund. (2) P . Radlick and S. Winstein, J . A m . Chem Soc., 86, 1866 (1964). (3) (a) S. Winstein and J. Sonnenberg, ibid., 81, 8524 (1959); (b) i b i d . , 88, 3235, 3244 (1961). (4) R . J. Piccolini and S . Winstein, Tehahcdron Suppf., No. 3,423 (1963) (5) While the corresponding carbanion is of even greater interest, good routes t o this species are still under investigation (6) For contrast, the corresponding delocalization energies for the anions are 0.824, 0.000, 1.464, and 2.472, respectively.

COMMUNICATIONS TO THE EDITOR

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Thus, a rather clear prediction may be made in favor of the three-center cation B.

A

B

C

D

Rates of acetolysis of the epimeric I-C-OTs and I-T-OTs give evidence of anchimeric acceleration of solvolysis of the stereoelectronically favorable cis epimer.3 Thus, first-order rate constants a t 75.0” (I-C-OTs > I-T-OTs, 52: 1) for acetolysis of ca. 0.007 M I-OTs in acetic acid, 0.01 M in sodium acetate, are 1.23 X l o p 4 and 2.37 X set.-' for I-C-OTs and I-T-OTs, respectively. The product from acetolysis of 0.04 M I-C-OTs in 0.07 iM sodium acetate in acetic acid for 20 reaction half-lives a t 75.0” was isolated by conventional work-up and lithium aluminum hydride reduction of the acetate. Analytical and preparative V.P.C. on XF-1150 silicone nitrile on ‘Chromosorb W columns showed that three alcohols, X (730/,), Y (18%), and 2 (5%), and an olefin (4%) were produced. The olefin was identical with the cis bismethylene adduct IV from 1,3,6-cyclooctatriene.z The major product alcohol X was pure I-COH as proved by V.P.C. behavior, melting point, infrared, and n.m.r. spectra, and melting point and mixture melting point of the I-OTs derivative. The formation of I-C-OH is highly stereospecific, no I-TOH being detected.

Vol. 86

8.49 peak corresponded to only 2 protons, and the aproton signal was now simplified to a triplet. In contrast to alcohol Y from solvolysis of deuterated I-C-d-OTs, the recovered I-C-OH from the I-Cd-OTs showed a rather substantial development of cyclopropane methylene proton. The average of a series of integrations indicated 0.52 f 0.03 cyclopropane methylene proton a t r 10.3. The evidence for anchimeric assistance of solvolysis of I-C-OTs and the stereospecificity in the formation of the two major products, I-C-OH and alcohol Y (II), suggest that these arise from a nonclassical rather than a classical carbonium ion. The deuterium scrambling in the I-C-OH product from I-C-d-OTs is uniquely in accord with a three-center ion (A or B). Fully protonated I-C-OH shows 2.0 protons a t r 10.3, and the predicted number of protons a t r 10.3 in the I-C-OH from tetradeuterated I-C-d-OTs is 0.50, 0.50, 0.67, and 1.2-for ions A, B, C, and D, respectively. The formation of a product like I1 is predicted only from ion B since this is the only one with the necessary C- 3-C-7 interzction. Thus, the evidence is uniquely in accord with the three-center ion B, the one also predicted from theoretical considerations. Ion B is a “trishomocyclopropenyl” type analogous to ?on V from cis-3-bicyclo [3.l.O]hexyl p-toluenesulfonate.3 -Evidence that alkyl-substituted examples of this latter variety of nonclassical ion, VI and VII, occur in acetolysis of neothujyl and neoisothujyl toluenesulfonates has just been published by Norin.’ The very high relative reactivities of the “cis” epimers and the unique nature of the products as regards stereochemis-

DmD -____-

D*D

OT8 I-C-d-OTs

D-d

111

The minor product alcohol 2 proved similar in V.P.C. behavior and similar. but not identical, in infrared spectrum with the hydrogen-shifted alcohol I11 derived from hydroboration-oxidationZ of the 1,3,6-~yclooctatriene bisadduct IV. Thus, there is some indication that 2 is one of the I11 epimers. Alcohol Y, m.p. 147-148”, analyzing correctly for CI0H16O,is also one we have not yet synthesized. However, infrared and n.m.r. spectra and mechanistic considerations suggest it is the hydrindanol 11. The n.m.r. spectrum of alcohol Y showed signals for 2 cyclopropane-methylene protons a t T 9.75, 2 cyclopropane tertiary protons a t r 9.1 (broad peak), 4 methylene protons and c6) a t r 8.49, 6 protons (C-2, C-3, C-7, and C-8) a t r 7.5-8.3 (very broad complex multiplet), and the cyproton a t r 5.98 (broad ill-resolved multiplet). When alcohol Y was isolated from solvolysis of the tetradeuterio-I-C-d-OTs. the T 9.75 signal was nearly absent, the r 9.1 signal was sharper and narrower, the r

(c,

try and structure are in striking accord with ions VI and VI1 and not explicable on the basis of classical cations. I

I

VI

VI1

L

VI11

A case with considerable analogy to the present one involving I-C-OTs and ion B seems to exist in the literature,* although the case in point was not interpreted in terms of a nonclassical ion. Solvolysis of cis-3-bicyclo [5.1.0]octyl bromobenzenesulfonate is qnalitatively much more rapid than that of the trans epimer (7) T.Norin, Tetrahedron Letters, No. 1, 37 (1964). (8) A . C. Cope, S. Moon, and C . H. Park, J. A m . Chem. Soc., 84, 48RO (1962).

May 5, 1964

COMMUNICATIONS TO THE EDITOR

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synthesis of boron-substituted nitrogen heterocyclic compounds has been initiated in our laboratories. We now wish to report the synthesis of some boron-substituted pyrimidines. Compounds of this type have not been prepared previously. l 1 Treatment of 5-brom0-2,4-&ihydroxypyrimidine~~ (9) U S. Rubber Company Foundation Postgraduate Fellow in Physical with phosphorus oxychloride and N,N'-dimethylaniand Engineering Science for 1961-1962. line gave 5-bromo-2,4-dichloropyrimidine(I), I 2 b.p. CONTRIBUTION No. 1647 S. WINSTEIN 75-80' (0.4 mm.), in 91% yield. Sodium methoxide O F CHEMISTRY P. BRUCK DEPARTMENT readily converted I to 5-bromo-2,4-dimethoxypyrimiOF CALIFORXIA PHILLIP RADLICK~ UNIVERSITY dine (IIa)j12m.p. 63-64'. The lithium compound Los ANGELES 24, CALIFORNIA R. BAKER IIIa, prepared by Langley's method,13 was caused to RECEIVEDMARCH6, 1964 react in situ with freshly distilled trimethyl borate or tributyl borate to give 2,4-dimethoxy-5-pyrimidineboronic acid (IVa), m.p. 115-117'. Anal. Calcd. for CsHgBNz04~0.5HzO: C, 37.3; H , 5.18; N, 14.5. Boron-Substituted Pyrimidines' Found: C, 37.1; H, 5.23; N , 14.5. An infrared spectrum of IVa had bands a t 1350 and 1250 cm.-', Sir: which were assigned to the B-0 and B-C stretching I t has been reported that when boron is localized frequencies, respectively. The B-0 deformation mode within cancerous tissue in the form of some suitable was located near 810 cm.-l and the boron-aryl sharp derivatives,2 the tumor cells are destroyed by the disabsorption band was also noted a t 1435 cm.-1.14 sipation of a-particles resulting from the neutroninduced disintegration of B lo (naturally occurring boron contains 18.84y0 of B'O isotope). Many investigators have since synthesized a number of boron-containing organic compounds including azo dyes, diboronic acids, bromine-, sulfur-, or nitrogen-substituted aroI IIa,R=CHs IIIa,R=CHs matic boronic acids,5amino acids,6boronic anhydride^,^ b,R=CeHa-CH2 b,R-CsH&-CHz as well as many heterocyclic boron compounds.8 Some 1 of these compounds have already been evaluated in animalsQbsd and in human patient^,^"^^^^ and a few have shown to be p r o m i ~ i n g . ~As ~ , ~the future success of neutron-capture therapy may well depend on the design v 1 of boron-substituted antimetabolites (which can be V IVa,R = CHs preferentially bound or incorporated into the structures b,R=CsH6-CHz of growing neoplasms),10 a program involving the

and the two very predominant alcohol products are produced completely stereospecifically as the cis epimers. The "trishomocyclopropenyl" cation VI11 provides an explanation for the reactivity and the observed stereochemistry.

(1) This investigation was supported by the Cancer Chemotherapy Na. tional Service Center, National Cancer Institute of the National Institutes of Health, Public Health Service (Contract SA-43-ph-3025). (2) For "neutron-capture" theory, see, e g . : (a) P. G. Kruger, Proc N a t l . Acad. Sci , 96, 181 (1940); (b) P . A. Zahl and F. S. Cooper, Science, 98, 64 (1941); (c) P . A. Zahl and F . S . Cooper, Radiology, S I , 673 (1941); (d) W. H . Sweet and M. Javid, J . Neurosurg., 9, 200 (1952); (e) P . G. Kruger, Radialion R e s . . 8, 1 (1955); (f) W. Gerrard, "The Organic Chemistry of Boron," Academic Press, New York, N . Y., 1961. pp. 76-201; (9) G. Milhaud, Maroc M e d . , 41, 295 (1962). (3) (a) H. R Snyder and C . Weaver, J . A m . Chem. Soc , I O , 232 (1948); (h) H. Gilman. L . Santucci, D. R. Swayampati, and R . 0. Ranck, i b i d . , 19, 2898, 3077 (1957). (4) (a) H. R . Snyder and S. L. Meisel, ibid., 70, 774 (1948); (b) D . R . Nielsen and W. E . McEwen, ibid.. 79, 3081 (1957); (c) A. H . Soloway, i b i d . , 89, 2442 (1960). ( 5 ) (a) L Santucci and H . Gilman, i b i d . , 80, 193 (1958); (h) A. H . Soloway, ibid., 81, 3017 (1959); (c) A. H. Soloway and P . Szabody, J. Org. Chem., 26, 1683 (1960). (6) H . R . Snyder, A. J. Reedy, and W. J . Lennarz, J . A m . Chem. Soc., 8 0 , 835 (1958) (7) H. R . Snyder, M. S. Konecky, and W . J . Lennarz, ibid., 80, 3611 (1958). (8) (a) S S. Chissick, M. J. S . Dewar, and P. M Maitlis. ibid., 81, 6329 (1959); (b) E . Nyilas and A. H. Soloway, i b i d . , 81, 2681 (1959); (c) R . T. Hawkins and H. R . Snyder, ibid., 89, 3863 (1960); (d) M. J . S. Dewar and R . C . Dougherty, ibid., 84, 2648 (1962); (e) M. J . S . Dewar and W. H. Poesche, ibid.. 86, 2253 (1963); (f) M J . S. Dewar and P. J. Grisdale, J . Org. Chem., 98, 1759 (1963). Earlier articles were cited by W. Gerrard, ref. 2f. (9) (a) L. E Farr, W. Haymaker, W. Calvo, Y. L. Yamamoto, and S W . Lippincott, Acta Nerrropalh. (Berlin), 1, 34 (1961); (b) A. H . Soloway, R . L. Wright, and J . R . Messer, J . Pharmacol E x p l l . Therap., 184, 117 (1961); (c) W. H. Sweet, A. H. Soloway, and R . L. Wright, ibid , 181, 263 (1962); (d) A. H . Soloway, B. Whitman. and J . R . Messer, J. Med. Pharm. Chem., 6, 191 (1962); (e) W. H . Sweet, A. H. Soloway, and G. L Brownell. A c f a Radiol., 1 ( 2 ) , 114 (1963), and referencescited therein. (10) C. A. Nichol, Abstracts, 142nd National Meeting of the American Chemical Society, Atlantic City, K .J., Sept., 1962. p. 1 8 - 0

2,4-Dibenzyloxy-5-pyrimidineboronic acid (IVb) was similarly prepared from I via 2,4-dibenzyloxy-5-bromopyrimidine (IIb; 59y0 yield, m.p. 87-89'. Anal. Calcd. for Cl8HI6BrN2O2:C, 58.2; H , 4.04; N, 7.55. Found: C, 58.2; H , 4.00; N, 7.50) and the lithium derivative IIIb. Since IVb was difficult to purify, it was converted directly to 5-uracilboronicacid (V) by catalytic hydrogenation. Compound V was isolated as a hemihydrate. Anal. Calcd. for C4H5BNzO4.0.5HZ0 : c, 29.1; H , 3.64; N , 17.0. Found: C, 29.3; H, 3.54; N, 17.4. Ultraviolet properties of V showed maxima a t 262 mp ( e 10,600, pH 1) and a t 284 mp ( e 5600, pH 11). The product decomposed slowly around 330". The structure of 5-uracilboronic acid (V) was further confirmed by oxidation to 5-hydroxyuracil (VI) according to the procedure of Letsinger and Dandegaonker for the conversion of 8-quinolineboronic acid to 8hydroxyquinoline.15 Compound VI was identical with (1 1) Attempted preparations of boron-substituted purine and pyrimidine have been discussed (see ref. 5h). (12) G. E. Hilbert and E. F. Jansen, J . A m . Chem. Soc., 66, 134 (1934) (13) B. W. Langley, i b i d . , 1 8 , 2136 (1956). (14) (a) L. J. Bellamy. W. Gerrard, M. F. Lappert, and R . 1.. Williams. J . Chem. Soc., 2412 (1958); (b) R . M Washburn, E Leven, C . F Albright, F. A Billig, and E. S Cernak, Advances in Chemistry, No. 2 3 , American Chemical Society. Washington, D. C , 1959, p . 112; (c) L. J Bellamy, "The Infrared Spectra of Complex Molecules." John Wiley and Sons,Inc., New York, N . Y . , 1960, p. 348 (15) R L. Letsinger and S. H Dandegaonker, J A m Chem. Soc.. 81, 498 (1959).